Positive modulators of nicotinic receptor agonists

ABSTRACT

Compounds of Formula I                    
     wherein R 1a , R 1b , R 2b , R 3b , R 3a , R 2a , B 1 , B 2 , Z, A 2  and A 1  are as defined in the specification, enantiomers thereof, pharmaceutically-acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, especially for treatment of conditions associated with reductions in nicotinic transmission. Compounds of the invention enhance the efficacy of agonists at nicotinic receptors.

REFERENCE TO RELATED APPLICATIONS

This is a Section 371 filing of International Application No.PCT/SE00/02149 filed Nov. 1, 2000, pending, which claims priority underthe Paris Convention to Application No. 9903996-8 filed in Sweden onNov. 3, 1999.

The present invention relates to novel compounds or pharmaceuticallyacceptable salts thereof, processes for preparing them, pharmaceuticalcompositions containing them and their use in therapy. The novelcompounds referred to are positive modulators of nicotinic receptoragonists, said positive modulator having the capability to increase theefficacy of the said nicotinic receptor agonists.

BACKGROUND

Cholinergic receptors normally bind the endogenous neurotransmitteracetylcholine (ACh), thereby triggering the opening of ion channels. AChreceptors in the mammalian central nervous system can be divided intomuscarinic (mAChR) and nicotinic (nAChR) subtypes based on the agonistactivities of muscarine and nicotine, respectively. The nicotinicacetylcholine receptors are ligand-gated ion-channels containing fivesubunits (for reviews, see Colquhon et al. (1997) Advances inPharmacology 39, 191-220; Williams et al. (1994) Drug News &Perspectives 7, 205-223; Doherty et al. (1995) Annual reports inMedicinal Chemistry 30, 41-50). Members of the nAChR gene family havebeen divided into two groups based on their sequences; members of onegroup are considered β subunits, while a second group are classified asα subunits (for reviews, see Karlin & Akabas (1995) Neuron 15,1231-1244; Sargent (1993) Annu. Rev. Neurosci. 16, 403-443). Three ofthe α subunits, α7, α8 and α9, form functional receptors when expressedalone and thus presumably form homooligorneric receptors.

An allosteric transition state model of the nAChR involves at least aresting state, an activated state and a “desensitized” closed channelstate (Williams et al., supra; Karlin & Akabas, supra). Different nAChRligands can thus differentially stabilize the conformational state towhich they preferentially bind. For example, the agonists ACh and(−)-nicotine stabilize the active and desensitized states.

Changes of the activity of nicotinic receptors has been implicated in anumber of diseases. Some of these, e.g. myasthenia gravis and ADNFLE(autosomal dominant nocturnal front lobe epilepsy) (Kuryatov et al.(1997) J. Neurosci. 17(23):9035-47), are associated with reductions inthe activity of nicotinic transmission either through a decrease inreceptor number or increased desensitization, a process by whichreceptors become insensitive to the agonist. Reductions in nicotinicreceptors have also been hypothesized to mediate cognitive deficits seenin diseases such as Alzheimer's disease and schizophrenia (Williams etal., supra). The effects of nicotine from tobacco are also mediated bynicotinic receptors. Increased activity of nicotinic receptors mayreduce the desire to smoke.

The use of compounds which bind nicotinic acetylcholine receptors in thetreatment of a range of disorders involving reduced cholinergic functionsuch as Alzheimer's disease, cognitive or attention disorders, attentiondeficit hyperactivity disorders, anxiety, depression, smoking cessation,neuroprotection, schizophrenia, analgesia, Tourette's syndrome, andParkinson's disease has been discussed in McDonald et al. (1995)“Nicotinic Acetylcholine Receptors: Molecular Biology, Chemistry andPharmacology”, Chapter 5 in Annual Reports in Medicinal Chemistry, vol.30, pp. 41-50, Academic Press Inc., San Diego, Calif.; and in Williamset al., supra.

However, treatment with nicotinic receptor agonists which act at thesame site as ACh is problematic because ACh not only activates, but alsoblocks receptor activity through processes which include desensitization(for a review, see Ochoa et al. (1989) Cellular and MolecularNeurobiology 9, 141-178) and uncompetitive blockade (open-channelblock); Forman & Miller (1988) Biophysical Journal 54(1):149-58.Furthermore, prolonged activation appears to induce a long-lastinginactivation. Therefore agonists of ACh can be expected to reduceactivity as well as enhance it. At nicotinic receptors in general, and,of particular note, at the α7-nicotinic receptor, desensitization limitsthe duration of current during agonist application.

Disclosure of the Invention

It has surprisingly been found that certain compounds can enhance theefficacy of agonists at nicotinic receptors. It is believed thatcompounds having this type of action (hereinafter referred to as“positive modulators”) will be particularly useful for treatment ofconditions associated with reductions in nicotinic transmission. In atherapeutic setting such compounds could restore normal interneuronalcommunication without affecting the temporal profile of activation. Inaddition, they would not produce long-term inactivation as prolongedapplication of agonist may.

According to the invention it has been found that compounds of FormulaI:

wherein,

R^(1a), R^(1b), R^(3a) and R^(3b) independently represent hydrogen, orC₁-C₄ alkyl;

R^(2a) and R^(2b) independently represents hydrogen, C₁-C₄ alkyl, orCH₂CN;

A¹ represents oxygen, sulfur, or NR^(4a);

B¹ represents oxygen, sulfur, or NR^(4b);

R^(4a) represents hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl; or togetherR^(3a) and R^(4a) form a ring;

R^(4b) represents hydrogen, C₁-C₄ alkyl, C₂-C₄ alkenyl; or togetherR^(3b) and R^(4b) form a ring;

A² and B² independently represent C(O), C(NH), OC(O), NHC(O), NHC(S),SO₂, or a bond;

Z represents (CH₂)_(n)Y(CH₂)_(m);

n and m are independently 0-4;

Y represents oxygen, sulfur, NR⁵, CHR⁶, Ar, or Ccy;

Ccy represents a 5-10 membered carbocycle including cyclopentane andadamantane;

Ar represents phenyl, naphthyl; or a 5- or 6-membered heterocyclic ringcontaining zero to four nitrogens, zero to one sulfurs and zero to oneoxygens;

Ar is optionally substituted with one or more substituents selectedfrom: hydrogen, halogen,

C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, CN, NO₂, CF₃, CR⁷, NR⁸R⁹, andCOOR¹⁰;

R⁷, R⁸ and R⁹ are independently hydrogen, C₁-C₄ alkyl, aryl, heteroaryl,C(O)R¹¹, C(O)R¹²,

SO₂R¹³, or, R⁸ and R⁹ together may be (CH₂)_(j)Q(CH₂)_(k), where

Q is oxygen, sulfur, NR¹⁴, or a bond;

j is 2-4;

k is 0-2;

R⁵, R⁶, R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are independently hydrogen, C₁-C₄alkyl, aryl, or heteroaryl;

or an enantiomer thereof, and pharmaceutically acceptable salts thereof,enhance the efficacy of agonists at nicotinic receptors.

Preferred compounds of the invention include the following:

1,3-Bis(indolyl-5-oxymethyl)benzene;

N,N′-Di(5-indolyl)-1,3-adamantanedicarboxamide;

or an enantiomer thereof, and pharmaceutically acceptable salts thereof.

Unless otherwise indicated, the C₁-C₄ alkyl groups referred to herein,e.g., methyl, ethyl, n-propyl, n-butyl, i-propyl, i-butyl, t-butyl,s-butyl, may be straight-chained or branched, and the C₃-C₄ alkyl groupsmay also be cyclic, e.g., cyclopropyl, cyclobutyl.

Unless otherwise indicated, the C₂-C₄ alkenyl groups referred to hereinmay contain one or two double bonds, e.g., ethenyl, i-propenyl,n-butenyl, i-butenyl, allyl, 1,3-butadienyl. Unless otherwise indicated,the C₂-C₄ alkynyl groups referred to herein contain one triple bond,e.g., ethynyl, propynyl, 1-or 2-butynyl.

Halogen referred to herein may be fluoride, chloride, bromide, oriodide.

The compounds of the invention have the advantage that they may be lesstoxic, be more efficaous, be longer acting, have a broader range ofactivity, be more potent, produce fewer side effects, are more easilyabsorbed or have other useful pharmacological properties.

Methods of Preparation

In the reaction schemes and text that follow, R^(1a), R^(1b), R^(2a),R^(2b), R^(3a), R^(3b), A¹, A², B¹, B², and Z, unless otherwiseindicated, are as defined above for formula I. The compounds of formulaI may be prepared according to the methods outlined in Schemes I and II.

Compounds of formula I may be prepared from compounds of formula IIIa orIIIb, wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b), A¹, A², B¹and B² are as defined in formula I, by reaction with an intermediate offormula IIa or IIb, wherein L^(a) or L^(b) is a suitable leaving grouprepresenting halogen, triflate (TfO), methanesulfonate (MsO), orp-toluenesulfonate (pTsO) and R^(1a), R^(1b) R^(2a), R^(2b), R^(3a),R^(3b), A¹, A², B¹, B², and Z are as defined in formula I, in thepresence of a suitable base and solvent. Intermediates of formula IIa orIIb may be prepared from compounds of formula IIIa or IIIb, whereinR^(1a), R^(1b), R^(2a), R^(2b), R^(3a), R^(3b), A¹, and B¹ are asdefined in formula I, by selective reaction of one of the leaving groupsof a compound of formula IV, wherein L^(a) and L^(b) are suitableleaving groups independently representing halogen, triflate (TfO),methanesulfonate (MsO), or p-toluenesulfonate (pTsO) and A², B² and Zare as defined in formula I, in the presence of a suitable base andsolvent. Suitable bases include sodium carbonate (Na₂CO₃), cesiumcarbonate (Cs₂CO₃), potassium carbonate (K₂CO₃), triethylamine (TEA) orN,N-diisopropylethylamine (DIPEA). Suitable solvents for the reactioninclude N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP),acetonitrile (ACN), dimethylsulfoxide (DMSO) or tetrahydrofuran (THF).The reaction is preferably performed at a temperature of 0-100° C. andmost preferably at ambient temperature.

Intermediates of formula IIa or IIb may be prepared from compounds offormula IIIa or IIIb, wherein R^(1a), R^(1b), R^(2a), R^(2b), R^(3a),R^(3b), A¹ and B¹ are as defined in formula I, by condensation with acompound of formula IVa or IVb, wherein N═C═O is an isocyanate group andL^(a) or L^(b) are suitable leaving groups (or synthetic precursors)representing halogen, triflate (TfO), methanesulfonate (MsO), orp-toluenesulfonate (pTsO) and A², B², and Z are as defined in formula I,in the presence of a suitable solvent. Suitable solvents for thereaction include N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP),acetonitrile (ACN), dimethylsulfoxide (DMSO), tetrahydrofuran (THF),chloroform, ethyl acetate (EtOAc), ethanol (EtOH) or methanol (MeOH).The reaction is preferably performed at a temperature of 0-100° C. andmost preferably at ambient temperature.

Compounds of formula IIIa and IIIb are either commercially available ormay be prepared by methods known to one skilled in the art (see, forexample, ‘Indoles: Reactions and Synthesis’ in ‘Heterocyclic Chemistry’,3^(rd) Edition, J. A. Joule, K. Mills, and G F. Smith, (Pub.) StanleyThornes Ltd. (1998) and references therein).

Compounds of formula IIIa and IIIb, wherein A¹ represents NR^(4a) wheretogether R^(3a) and R^(4a) form a ring and/or wherein B¹ representsNR^(4b) where together R^(3b) and R^(4b) form a ring, may be prepared bymethods known to one skilled in the art (see, for example, J. E. Macor,J. T. Froman, R. J Post, K. Ryan, Tetrahedron Lett., 38, 1673-1676,1997).

Compounds of formula IV, IVa and IVb are commercially available or maybe prepared by methods known to one skilled in the art.

Where necessary, hydroxy, amino or other reactive groups may beprotected using a protecting group as described in the standard text,‘Protecting Groups in Organic Synthesis’, 3^(rd) Edition, T. W. Greeneand P. G. M. Wuts, 1999, J Wiley & Sons, Inc.

The above described reactions, unless otherwise noted, are usuallyconducted at a pressure of about one to about three atmospheres,preferably at ambient pressure (about one atmosphere). Unless otherwisestated, the above described reactions are conducted under an inertatmosphere, preferably under a nitrogen atmosphere.

The compounds of the invention and intermediates may be isolated fromtheir reaction mixtures by standard techniques.

Acid addition salts of the compounds of formula I which may be mentionedinclude salts of mineral acids, for example the hydrochloride andhydrobromide salts; and salts formed with organic acids such as formate,acetate, maleate, benzoate, tartrate, and fumarate salts. Acid additionsalts of compounds of formula I may be formed by reacting the free baseor a salt, enantiomer or protected derivative thereof, with one or moreequivalents of the appropriate acid. The reaction may be carried out ina solvent or medium in which the salt is insoluble or in a solvent inwhich the salt is soluble, e.g., water, dioxane, ethanol,tetrahydrofuran or diethyl ether, or a mixture of solvents, which may beremoved in vacuum or by freeze drying. The reaction may be ametathetical process or it may be carried out on an ion exchange resin.The compounds of formula I exist in tautomeric or enantiomeric forms,all of which are included within the scope of the invention. The variousoptical isomers may be isolated by separation of a racemic mixture ofthe compounds using conventional techniques, e.g. fractionalcrystallization, or chiral HPLC. Alternatively the individualenantiomers may be made by reaction of the appropriate optically activestarting materials under reaction conditions which will not causeracemization.

The compounds of formula I, or an enantiomer thereof, andpharmaceutically acceptable salts thereof, may be used on their own orin the form of appropriate medicinal preparations for enteral orparenteral administration. According to a further aspect of theinvention, there is provided a pharmaceutical composition includingpreferably less than 80% and more preferably less than 50% by weight ofa compound of the invention in admixture with an inert pharmaceuticallyacceptable diluent or carrier.

Examples of diluents and carriers are:

for tablets and dragees: lactose, starch, talc, stearic acid; forcapsules: tartaric acid or lactose;

for injectable solutions: water, alcohols, glycerin, vegetable oils; forsuppositories: natural or hardened oils or waxes.

There is also provided a process for the preparation of such apharmaceutical composition, which comprises mixing the ingredients.

It will be understood that a pharmaceutical composition comprising apositive modulator of a nicotinic receptor agonist together with apharmaceutically acceptable carrier said positive modulator having thecapability to increase the efficacy of the said receptor agonist. Forthe purposes of the present invention, the term “positive modulator” or“positive modulator of a nicotinic receptor agonist” shall be understoodas a compound having the capability to increase the maximum efficacy ofa nicotinic receptor agonist.

It will be understood that the invention includes compositionscomprising either a positive modulator as the only active substance,thus modulating the activity of endogenous nicotinic receptor agonistssuch as acetylcholine or choline, or a positive modulator in combinationwith a nicotinic receptor agonist. Thus, the said pharmaceuticalcompositions containing a positive modulator of a nicotinic receptoragonist may, in addition comprise a nicotinic receptor agonist.

In a preferred form of the invention, the said nicotinic receptoragonist is an α7-nicotinic receptor agonist. Example of an α7-nicotinicreceptor agonist is(−)-Spiro[1-Azabicyclo[2.2.2.]Octane-3,5*-Oxazolidine]-2*-One. Severalα7-nicotinic receptor agonists are known in the art, e.g. from WO96/06098, WO 97/30998 and WO 99/03859.

A further aspect of the invention provides a method for the treatment ofa condition associated with reduced nicotine transmission, byadministering to a patient in need of such treatment, a medicallyeffective amount of a positive modulator of a nicotinic receptoragonist, said positive modulator having the capability to increase theefficacy of the said nicotinic receptor agonist.

It will be understood that the methods of treatment of this inventionincludes either a positive modulator as the only active substance, thusmodulating the activity of endogenous nicotinic receptor agonists suchas acetylcholine or choline, or a positive modulator administeredtogether with a nicotinic receptor agonist.

In another preferred form of the invention, the said method of treatmentincludes a nicotinic receptor agonist, which is an α7-nicotinic receptoragonist. Example of an α7-nicotinic receptor agonist is(−)-Spiro[1-Azabicyclo[2.2.2.]Octane-3,5 *-Oxazolidine]-2*-One. Severalα7-nicotinic receptor agonists are known in the art, e.g. from WO96/06098. WO 97/30998 and WO 99/03859.

Utility

A further aspect of the invention is the use of compound according tothe invention in the manufacture of a medicament for the treatment orprophylaxis of a condition associated with reduced nicotinic receptortransmission or a condition associated with reduced nicotinic densitywhich could be one of the below mentioned diseases or conditions whichcomprises administering a therapeutically effective amount of compoundsaccording to the invention to a patient.

It will be understood that the use includes compositions comprisingeither a positive modulator as the only active substance, thusmodulating the activity of endogenous nicotinic receptor agonists suchas acetylcholine or choline, or a positive modulator in combination witha nicotinic receptor agonist. Thus, the said use of pharmaceuticalcompositions containing a positive modulator of a nicotinic receptoragonist may, in addition comprise a nicotinic receptor agonist.

In a preferred form of the invention, the use of the said nicotinicreceptor agonist is represented by an α7-nicotinic receptor agonist.Example of an α7-nicotinic receptor agonist is(−)-Spiro[1-Azabicyclo[2.2.2.]Octane-3,5*-Oxazolidine]-2*-One. Severalα7-nicotinic receptor agonists are known in the art, e.g. from WO96/06098, WO 97/30998 and WO 99/03859.

Examples of diseases or conditions include schizophrenia, mania andmanic depression, anxiety, Alzheimer's disease, learning deficit,cognition deficit, attention deficit, memory loss, Lewy Body Dementia,Attention Deficit Hyperactivity Disorder, Parkinson's disease,Huntington's disease, Tourette's syndrome, jetlag, and nicotineaddiction (including that resulting from exposure to products containingnicotine).

It will be understood that the said positive modulator can beadministered either with the purpose of acting on endogenous nicotinereceptor agonists such as acetylcholine or choline, or in combinationwith an exogenous nicotinic receptor agonist.

A further aspect of the invention relates to a compound for treating orpreventing a condition or disorder as exemplified above arising fromdysfunction of nicotinic acetylcholine receptor neurotransmission in amammal, preferably a human, compositions comprising either a positivemodulator as the only active substance, thus modulating the activity ofendogenous nicotinic receptor agonists, or a positive modulator incombination with a nicotinic receptor agonist. Thus, the said use ofpharmaceutical compositions containing a positive modulator of anicotinic receptor agonist may, in addition comprise a nicotinicreceptor agonist, effective in treating or preventing such disorder orcondition and an inert pharmaceutically acceptable carrier.

Experimental Methods

The activity of the compounds of the invention may be measured in thetests set out below:

(a) Xenopus Oocyte Current Recording

The Xenopus oocyte has provided a powerful means of assessing thefunction of proteins thought to be subunits of ligand-gatedion-channels. Injection of RNA transcribed from cDNA clones encoding theappropriate receptor subunits, or injection of cDNA in which the codingsequence is placed downstream of a promoter, results in the appearanceof functional ligand-gated ion-channels on the surface of the oocyte(see e.g. Boulter et al. (1987) Proc. Natl. Acad. Sci. U.S.A. 84,7763-7767).

Consequently, one convenient technique to assess the enhancement ofnicotinic efficacy is two-electrode voltage-clamp recording from Xenopusoocytes expressing α7-nicotinic receptors from cRNA.

Xenopus laevis frogs (Xenopus I, Kalamazoo, Mich.) were anesthetizedusing 0.15% tricaine. Oocytes were removed to OR2 solution (82 mM NaCl,2.5 mM KCl, 5 mM HEPES, 1.5 mM NaH₂PO₄, 1 mM MgCl₂, 0.1 mM EDTA; pH7.4). The oocytes were defolliculated by incubation in 25 ml OR2containing 0.2% collagenase 1A (Sigma) two times for 60 min on aplatform vibrating at 1 Hz and stored in Leibovitz's L-15 medium (50μg/ml gentomycin, 10 Units/ml penicillin, and 10 μg/ml streptomycin).Approximately 50 ng of cRNA was injected in each oocyte the followingday. cRNA was synthesised from cDNA using Message Machine (purchasedfrom Abion).

The external recording solution consisted of 90 mM NaCl, 1 mM KCl, 1 mMMgCl₂, 1 mM BaCl₂, 5 mM HEPES; pH 7.4. Two-electrode voltage-clamprecording was carried out using an Oocyte Clamp amplifier (OC 725C;Warner Instrument, Hamden, Conn.). Oocytes were impaled with twoelectrodes of 1-2 MΩ tip resistance when filled with 3M KCl. Recordingswere begun when membrane potential became stable at potentials negativeto −20 mV (resting membrane potentials are less negative when Ba⁺⁺replaces Ca⁻⁺ in bathing solutions). Membrane potential was clamped at−80 mV. ACh was purchased from Sigma. Oocytes were continuously perfused(5 ml/min) with recording solution with or without ACh.

Current amplitude was measured from baseline to peak. EC₅₀ values,maximal effect, and Hill slopes were estimated by fitting the data tothe logistic equation using GraphPad Prism (GraphPad Software, Inc., SanDiego, Calif.).

Increases in agonist efficacy elicited by a positive modulator can becalculated in two ways:

(1) As percent potentiation of current amplitude which is defined as100(I_(m)-I_(c))/I_(c) where I_(m) is current amplitude in the presenceof modulator and I_(c) is current in the absence of modulator.

(2) As percent potentiation of “area under curve” of an agonist trace,which is the integration of net current over time. Area under the curveis a common representation of the total ion flux through the channel.

(b) Ca²⁺ Flux Imaging

Imaging of Ca²⁺ flux through nAChR α7 receptors transiently expressed ina cell line is another means of assaying modulator activity.

Cells expressing α7 receptors (for example HEK-293 cells or cellcultured neurons) are grown to confluence in 96 well plates and loadedwith fluo-3, a fluorescent calcium indicator. To screen for α7modulatory activity, the 96 well plate is placed in a fluorescenceimaging plate reader (FLIPR) and test compounds along with an α7 agonistare applied simultaneously to all well. Receptor activation is measuredby calcium influx into cells which is quantified by the increase influorescence intensity of each well, recorded simultaneously by theFLIPR. A modulatory effect is determined by the increase in fluorescenceover that of agonist alone. Similarly, to test for nAChR α7 agonistactivity, test compounds along with an α7 modulator are appliedsimultaneously to all wells. Receptor activation is measured by calciuminflux into cells which is quantified by the increase in fluorescenceintensity of each well, recorded simultaneously by the FLIPR. An agonisteffect is determined by the increase in fluorescence over that ofmodulator alone. Cell-cultured neurons are prepared according to thefollowing method: Eighteen day old Sprague-Dawley rat fetuses (E-18)were asceptically removed from the pregnant male, sacrificed, thefrontal cortices of the brains removed, the menniges stripped, and thecleaned cortex placed into cold HBSS. If hippocampus was desired, thehippocampus was dissected away from the cortex and then placed into coldHBSS. The tissues were mechanically dispersed, washed once in HBSS (200g for 30 minutes in 4° C.) resuspended in a modification of Sato'smedium supplemented with glutamine, antibiotics, potassium chloride,insulin, transferrin, selenium, and 5% heat-inactivated fetal bovineserum (FBS; endotoxin free) and plated into each of a 24-well plate(coated with poly-L-lysine). The wells could contain glass coverslipswhich were also coated with PLL. The plates were incubated at 37° C. ina CO₂ incubator. After 24 hours the medium was removed, fresh mediumadded, and the cells allowed to grow for at least another 11 days,feeding when necessary.

The compounds of the invention are compounds, which causes a 100%potentiation (2-fold increase) of baseline current (as described above),as measured baseline to peak at low concentration of Acetylcholine (30μM), indicating that they are expected to have useful therapeuticactivity. The compounds of the invention are also compounds, whichincrease the flux of Ca²⁺ when applied in the Ca²⁺ flux-imaging assay,as described above. Any increase of Ca²⁺ flux, caused by a compound ofthe invention, compared to the Ca²⁺ flux caused by an agonist alone (asmeasured in Fluorescence Intensity Units) indicates that they areexpected to have useful therapeutic activity.

The use of compounds of the invention have the advantage that they maybe less toxic, be more efficacious, be longer acting, have a broaderrange of activity, be more potent, produce fewer side effects, are moreeasily absorbed or have other useful pharmacological properties.

General Experimental Procedures

Commercial reagents were used without further purification. Mass spectrawere recorded following either chemical ionization (MS CI) orelectrospray (MS ES) ionization methods and are reported as m/z for theprotonated parent molecular ion (MH⁺). Room temperature refers to 20-25°C.

EXAMPLES

The following examples are preferred non-limiting examples embodyingpreferred aspects of the invention.

Example 1 1,3-Bis(indolyl-5-oxymethyl)benzene

To a solution of 5-hydroxyindole (0.133 g) in N,N-dimethylformamide (20ml) was added cesium carbonate (0.652 g) and α,α′-dibromo-m-xylene(0.132 g). The suspension was stirred under nitrogen at ambienttemperature overnight. Cesium salts were removed by filtration andwashed with acetone. The residue left on concentrating the combinedfiltrate and washings was chromatography over silica gel with a mixtureof ethyl acetate and hexanes and precipitated from ether with hexanes togive 0.1 g of the title compound. MS CI (MH⁺)=369.

Example 2 N,N′-Di(5-indolyl)-1,3-adamantanedicarboxamide

To a solution of 1,3-adamantanedicarboxylic acid (0.112 g) in chloroform(10 ml) at 0° C. was added thionyl chloride (0.18 g). The solution wasallowed to warm to room temperature overnight and reduced to a residueat reduced pressure. The residue was dissolved in dry tetrahydrofuranand concentrated twice more to remove excess thionyl chloride. To asolution of the resulting acid chloride in tetrahydrofuran (20 ml) at 0°C. was added 5-aminoindole (0.13 g) and triethylamine (0.1 g) and theresulting suspension was allowed to warm to room temperature overnight.The precipitated triethylamine hydrochloride was removed by filtrationand washed with tetrahydrofuran. The residue left on concentrating thecombined filtrate and washings was chromatographed over silica gel witha mixture of ethyl acetate and hexanes to give 0.16 g of the titlecompound. MS ES (MH⁺)=453.

What is claimed is:
 1. A compound of Formula I:

wherein: R^(1a) and R^(1b) represent hydrogen; R^(2a), R^(2b), R^(3a)and R^(3b) independently represents hydrogen or C₁-C₄ alkyl; A¹represents oxygen or sulfur; B¹ represents oxygen or sulfur; A² and B²independently represent C(O), C(NH), OC(O), NHC(O), NHC(S), SO₂, or abond; Z represents (CH₂)_(n)Y(CH₂)_(m); n and m are independently 0, 1,2, 3 or 4; Y represents Ar, or Ccy; Ccy represents cyclopentyl oradamantyl; Ar represents phenyl or naphthyl; Ar is optionallysubstituted with one or more substituents selected from: hydrogen,halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, CN or CF₃; or anenantiomer thereof, or a pharmaceutically-acceptable salt thereof.
 2. Acompound according to claim 1, said compound being:1,3-Bis(indolyl-5-oxymethyl)benzene;N,N′-Di(5-indolyl)-1,3-adamantanedicarboxamide; or an enantiomerthereof, or a pharmaceutically-acceptable salt thereof.
 3. A method forthe treatment of Alzheimer's disease, learning deficit, cognitiondeficit, attention deficit, memory loss, Attention Deficit HyperactivityDisorder, Lewy Body Dementia, anxiety, schizophrenia, or mania or manicdepression, Parkinson's disease, Huntington's disease, Tourette'ssyndrome, neurodegenerative disorders in which there is loss ofcholinergic synapse, jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,pain, or ulcerative colitis, comprising administering to a subjectsuffering therefrom a therapeutically-effective amount of a compoundaccording to claim
 1. 4. A pharmaceutical composition comprising acompound according to claim 1, in admixture with apharmaceutically-acceptable diluent or carrier.
 5. The pharmaceuticalcomposition according to claim 4, for the use in the treatment of humandiseases or conditions in which said composition has the capability toincrease the efficacy of a nicotinic, wherein said disease or conditionis selected from the group consisting of: Alzheimer's disease, learningdeficit, cognition deficit, attention deficit, memory loss, AttentionDeficit Hyperactivity Disorder, Lewy Body Dementia, anxiety,schizophrenia, or mania or manic depression, Parkinson's disease,Huntington's disease, Tourette's syndrome, neurodegenerative disordersin which there is loss of cholinergic synapse, jet lag, cessation ofsmoking, nicotine addiction including that resulting from exposure toproducts containing nicotine, pain, or ulcerative colitis.
 6. A methodfor the treatment of Alzheimer's disease, learning deficit, cognitiondeficit, attention deficit, memory loss, Attention Deficit HyperactivityDisorder, Lewy Body Dementia, anxiety, schizophrenia, or mania or manicdepression, Parkinson's disease, Huntington's disease, Tourette'ssyndrome, neurodegenerative disorders in which there is loss ofcholinergic synapse, jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,pain, or ulcerative colitis, comprising administering to a subjectsuffering therefrom a therapeutically-effective amount of thepharmaceutical composition according to claim
 4. 7. A method oftreatment of psychotic disorders or intellectual impairment disorders,in which activation of the α7 nicotinic receptor is beneficial whichcomprises administering a therapeutically effective amount of a compoundaccording to claim
 1. 8. The method according to claim 7, wherein thedisorder is Alzheimer's disease, learning deficit, cognition deficit,attention deficit, memory loss, Attention Deficit HyperactivityDisorder, Lewy Body Dementia, anxiety, schizophrenia, mania or manicdepression, Parkinson's disease, Huntington's disease, Tourette'ssyndrome, neurodegenerative disorders in which there is loss ofcholinergic synapse, jetlag, cessation of smoking, nicotine addictionincluding that resulting from exposure to products containing nicotine,pain, or ulcerative colitis.
 9. The method according to claim 8, whereinthe disorder is Alzheimer's disease.